#111 Mdmeo; n-methoxy-mda; 3,4-methylenedioxy-n-methyoxyamphetamine

SYNTHESIS: To a solution of 20.9 g methoxyamine hydrochloride in 75 mL MeOH (a strongly acidic solution) there was added 4.45 g 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.10 g sodium cyanoborohydride. There was the immediate formation of a solid phase, and the evolution of what appeared to be hydrogen cyanide. To this there were added about 4 mL 5% NaOH which brought the pH to the vicinity of 3 or 4. Another 1.0 g of sodium cyanoborohydride was added (no gas evolution this time) and stirring was continued at ambient temperature for 6 days. All was added to 500 mL H2O, acidified with 10 mL HCl, and extraction with 3x100 mL CH2Cl2 removed almost all the color. The aqueous phase was made basic with 25% NaOH, and extracted with 4x100 mL CH2Cl2. Evaporation of the solvent from these extracts yielded 1.8 g of a pale yellow oil which, on distillation at 90-95 deg C at 0.5 mm/Hg, gave a 1.6 g fraction of an absolutely white, viscous, clear oil. This was dissolved in 8 mL IPA and neutralized with concentrated HCl. The product was an exceptionally weak base, and appropriate end points must be respected on the external pH paper (yellow to red, rather than purple to orange). Anhydrous Et2O was added to the point of turbidity, and as soon as crystallization had actually started, more Et2O was added with stirring, for a net total of 200 mL. After a couple of h standing, the fine white crystalline 3,4-methylenedioxy-N-methoxyamphetamine hydrochloride (MDMEO) was removed by filtration, Et2O washed, and air dried to constant weight. There was obtained 1.7 g of a product with a mp of 143-146 deg C. The proton NMR was excellent with the N-methoxyl group a sharp singlet at 4.06 ppm. Anal. (C11H16ClNO3) N.

DOSAGE: greater than 180 mgs.

DURATION: unknown

EXTENSIONS AND COMMENTARY: Why the interest in the N-methoxy analogue of MDA? There are several reasons. One, this is an isostere of MDE and it would be interesting to see if it might serve as a primer to the promotion of the effectiveness of other drugs (see primer discussion under MDPR). In one experiment, wherein a 60 microgram dosage of LSD was used an hour and a half after a 180 milligram load of MDMEO, there was no augmentation of effects. Thus, it would appear not to be a primer. Another reason for interest was that the material, although having an extremely similar overall structure to most of the active MD-series compounds, is very much a weaker base. And MDOH, which is also a very much weaker base than MDA, still shows the action and potency of MDA. And, as this compound appears to be inactive, base strength is not a sole predictor of activity.

The ultimate reason for making MDMEO was, of course, that it could be made. That reason is totally sufficient all by itself.

#112 Mdmeoet; n-methoxyethyl-mda;

3,4-METHYLENEDIOXY-N-(2-METHOXYETHYL)AMPHETAMINE

SYNTHESIS: A crude solution of methoxyethylamine hydrochloride was prepared from 17.7 g methoxyethylamine and 20 mL concentrated HCl with all volatiles removed under vacuum. This was dissolved in 75 mL MeOH and there was added 4.45 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.3 g sodium cyanoborohydride. Concentrated HCl in MeOH was added as required to maintain the pH at about 6 as determined with external, dampened universal pH paper. About 4.5 mL were added over the course of 5 days, at which time the pH had stabilized. The reaction mixture was added to 400 mL H2O and made strongly acidic with an excess of HCl. After washing with 2x100 mL CH2Cl2 the aqueous phase was made basic with 25% NaOH, and extracted with 4x75 mL CH2Cl2. Removal of the solvent under vacuum yielded 6.0 g of an amber oil that was distilled at 110-120 deg C at 0.2 mm/Hg. There was obtained 4.7 g of a crystal-clear white oil that was dissolved in 30 mL IPA and neutralized with 45 drops of concentrated HCl producing a heavy mass of spontaneous crystals that had to be further diluted with IPA just to be stirred with a glass rod. These were diluted with 200 mL of anhydrous Et2O, removed by filtration, and washed with additional Et2O. After air drying there was obtained 4.9 g of 3,4-methylenedioxy-N-(2-methoxyethyl)amphetamine hydrochloride (MDMEOET) with a mp of 182.5-183 deg C. Anal. (C13H20ClNO3) N.

DOSAGE: greater than 180 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This is another example of the replacement of a neutral atom out near the end of a chain, with a more basic and a more polar one. MDMEOET would be called an isostere of MDBU in that it has the same shape, with a methylene unit (the CH2) replaced by an oxygen atom. No activity turned up with either compound, so nothing can be learned from this particular example of change of polarity.

#113 MDMP; a,a,N-TRIMETHYL-3,4-METHYLENEDIOXY-PHENETHYLAMINE;

METHYLENEDIOXYMEPHENTERMINE

SYNTHESIS: To a well stirred solution of 1.64 g of 1-(N-(benzyloxycarbonyl)amino)-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane (see under MDPH for its preparation) in 10 mL anhydrous THF there was added a suspension of 0.38 g LAH in 25 mL THF. All was held at reflux for 24 h, the excess hydride was destroyed by the addition of 1.5 mL H2O, and sufficient aqueous NaOH was added to make the reaction mixture basic and flocculant enough to be filterable. The inorganic solids were removed by filtration and, following washing with THF, the combined filtrate and washings were stripped of organic solvent under vacuum. The residue was dissolved in 100 mL Et2O and washed with 2x50 mL saturated aqueous NaHCO3. After drying the organic phase with anhydrous MgSO4, the solvent was removed under vacuum to give a yellow oil. This was dissolved in 50 mL absolute EtOH and neutralized with concentrated HCl. Removal of the solvent under vacuum yielded an off-white solid that was recrystallized from an EtOH/EtOAc mixture to provide 0.84 g of a,a,N-trimethyl-3,4-methylenedioxyphenethylamine hydrochloride (MDMP) with a mp of 206-208 deg C. The NMR spectrum showed the a,a-dimethyl pair as a singlet at 1.38 ppm. Anal. (C12H18ClNO2) C,H,N.

DOSAGE: above 110 mg.

DURATION: perhaps 6 hours.

QUALITATIVE COMMENTS: (with 60 mg) There was a faint, dull alerting at just over a half hour. The time sense was out of order, and an absence of visuals but a generalized attentiveness to my surroundings was suggestive of MDMA. Nothing remained at the six hour point.

(with 110 mg) There was a light-headedness, and a complete absence of libido. Nothing in any way psychedelic, but there are hints of discomfort (jaw tension) that will bear close watching at higher dosages. It might evolve at higher levels into something like MDMA.

EXTENSIONS AND COMMENTARY: This is one of several candidates for clinical use as a substitute for MDMA, but there will have to be a much broader study of its qualitative action in man. It is clearly not psychedelic at these modest levels, and in in vitro animal studies it was apparently inactive as a serotonin releaser. The warped logic for looking at phentermine analogs was discussed in the comments that concerned MDPH. The initials used here have been chosen with care. MDM should not be used as it has found some currency as an abbreviation for MDMA (Methylene-Dioxy-Methamphetamine). MDMP fits neatly with Methylene-Dioxy-Me-Phentermine.